B cells are characterized by their specific ability to produce antibodies. Therefore, the antibody-mediated immune responses are the major mechanism played by B cells. Indeed, as compared to T cells, B cells have not typically been considered to be a major source of cytokines. However, it is evident that B cells can also produce a wide spectrum of cytokines particularly under inflammatory conditions. We have identified inducible B cell subset that develops in response to inflammation and contributes to the improvement of ongoing inflammation through the production of cytokines. The cytokine-producing, inducible regulatory B cells termed "iBreg" possess the ability to not only control inflammatory immune responses but also inhibit atherosclerosis and tumor immunity. These findings suggest the coexistence of effector and regulatory B cells in several pathophysiological conditions. The long-term objective of this project is to identify the mechanism leading to iBreg development in order to provide a rationale in utilizing iBreg to improve several health problems. Our preliminary study has identified a previously unidentified unique IgM+ MHC class IIbright B cell population that resides in normal large intestine and expands markedly in response to inflammation. The unique B cells were recruited from immature transitional and recirculating naive B2 cell pools and could expand without differentiation into plasma cells. Interestingly, they developed both in antigen-independent manner and in SLPI (secretory leukocyte protease inhibitor) and BAFF (receptor of B cell activation factor from the TNF family)-dependent manners. These unique B cells shared some phenotypic and functional features with iBreg that has previously been shown to develop in mesenteric lymph nodes (MLN) only under inflammatory condition. Based on these data, we hypothesize that the unique intestinal B cells represent a precursor of iBreg, which differentiates from immature/naive B cells in the large intestine in the presence of SLPI (for inhibition of canonical NFkB pathway, NFkB1) and BAFF (for activation of alternative NFkB pathway, NF:B2) and then homes into MLN where their immune regulatory function is fully elicited. This grant application aims at investigating why MHC class IIbright B cells specifically expand in the contest of inflammation, how they develop, whether they represent an immediate precursor of iBreg, and how immune regulatory ability of MHC class IIbright B cell-derived iBreg is elicited. PUBLIC HEALTH RELEVANCE: Biological responses in our bodies are controlled by the interactions of many different cell types to suppress the development of undesirable health conditions (1). We have recently identified a novel cell subset termed iBreg, which is specifically induced under inflammatory conditions and is capable of improving the disease (2-4). This project aims at dissecting the mechanism involved in the development of iBreg. We believe that the study proposed would provide important intervention to develop a novel immune therapy for resolving diverse health problems, including infection, autoimmune diseases, cancer, and atherosclerosis.